OBJECTIVES: Tension-type headache (TTH) is the most common headache experienced by adults in Western society. Only 2 clinical trials of spinal manipulation for adult tension-type headache have been reported, neither of which was fully controlled. In 1 trial, spinal manipulation was compared to amitriptyline. There is an urgent need for well-controlled studies of chiropractic spinal manipulation for TTH. This trial was stopped prematurely due to poor recruitment. The purposes of this report are (1) to describe the trial protocol, as it contained several novel features, (2) to report the limited data set obtained from our sample of completed subjects, and (3) to discuss the problems that were encountered in conducting this study.

METHODS: A randomized clinical trial was conducted with a factorial design in which adult TTH sufferers with more than 10 headaches per month were randomly assigned to four groups: real cervical manipulation + real amitriptyline, real cervical manipulation + placebo amitriptyline, sham cervical manipulation + real amitriptyline, and sham cervical manipulation + placebo amitriptyline. A baseline period of four weeks was followed by a treatment period of 14 weeks. The primary outcome was headache frequency obtained from a headache diary in the last 28 days of the treatment period.

RESULTS: Nineteen subjects completed the trial. In the unadjusted analysis, a statistically significant main effect of chiropractic treatment was obtained (-2.2 [-10.2 to 5.8], P = .03) which was just below the 3-day reduction set for clinical importance. As well, a clinically significant effect of the combined therapies was obtained (-9 [20.8 to 2.9], P = .13), but this did not achieve statistical significance. In the adjusted analysis, neither the main effects of chiropractic nor amitriptyline were statistically significant or clinically important; however, the effect of the combined treatments was -8.4 (-15.8 to -1.1) which was statistically significant (P = .03) and reached our criterion for clinical importance.

CONCLUSION: Although the sample size was smaller than initially required, a statistically significant and clinically important effect was obtained for the combined treatment group. There are considerable difficulties with recruitment of subjects in such a trial. This trial should be replicated with a larger sample.

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Discussion

Tension-type headache is a highly prevalent chronic pain problem in Western society. Considerable research exists for medical approaches to prophylactic therapy, especially for CTTH. [13, 14, 19—23] Research on complementary/alternative therapies is, conversely, very sparse, whereas research on combinations of medical and complementary/alternative approaches is virtually nonexistent. Our trial was an attempt to address the need for such collaborative studies in a primary care setting. Our hypotheses were motivated by the theory that each of these therapies exerts effects on separate dimensions of the mechanisms thought to contribute to TTH: peripheral mechanisms might be addressed by chiropractic therapy, and central mechanisms might be addressed by amitriptyline. We expected that the combination of these two therapies might be more efficacious than either alone.

We were unable to reach our intended sample size and stopped the trial before its expected completion. We found that neither treatment on its own met our clinically important criterion of a reduction of at least 3 headaches, although the effect of the chiropractic treatment (effect = -2.2) in the unadjusted analysis was statistically significant. The group receiving the combination of amitriptyline and chiropractic met our a priori level of clinically important change. In the unadjusted analysis, this effect was not statistically significant; it became so in the adjusted analysis.

Our study had 2 novel features that distinguish it from other randomized, controlled trials of manual therapy. We used a factorial design which permitted an investigation of the effects of each therapy separately and in combination, while reducing the sample size needed for these three comparisons compared to a parallel groups design. The factorial design has been used in few clinical trials of chiropractic treatments to date. [51—53] This trial design included a placebo or sham version of each therapy. According to Vernon et al, [45] the sham cervical manipulation used in our trial had been shown to approximate the necessary criteria to qualify as a sham manipulation, delivered on a single occasion. While placebo groups are standard procedure for medication trials, this is the first time that a sham cervical manipulation group has been employed in a chiropractic clinical trial of TTH. As well, this is the first time that the combination of placebo medication and sham manual therapy procedure has been used in a true control group.

It appears that there was moderate success with the blinding of the subjects in this trial. In the previous trials of manipulation for TTH, Boline et al [37] used no placebo/sham group at all, whereas Bove and Nilsson [38] used only sham electrotherapy to balance both manual therapy groups. The results of our study indicate that a set of sham manipulative procedures can be successfully used in combination with a placebo medication in a clinical trial setting. It is not yet clear if this procedure alone (without placebo medication) will suffice as a successful sham therapy for a clinical trial.

Our trial was limited by the low number of participants we recruited over the approximately 2 1/2 years we ran the trial. We recruited from the general public using various forms of advertising including newspaper ads, radio ads, Web site posting on clinical trials and headache Web sites, public outreaches, and public transit ads. We also contacted approximately 200 clinics in the local area to solicit referrals. In the late stages of the trial, we were in the process of setting up referral sites in 2 hospital settings, but our feasibility projections required that the trial be closed rather than continue with these efforts.

Two situations stand out when we review our recruiting outcomes: the low number of calls at first contact (n = 636) and the substantial attrition of contacts to the point of randomization. A number of circumstances may have impacted the low number of calls from potential participants. Most people with TTH self-medicate [13—16] and the relapsing/remitting nature of the complaint may mean that this population is less likely to be interested in a clinical trial. The trial was conducted during a period of negative publicity about chiropractic treatment of the neck which may have influenced the decision to call in despite the fact that, at least for some conditions, people are willing to enter trials of alternative therapy. [54] In consultation with other clinical trials groups, we found that, similar to our situation, recruitment was difficult. This may indicate a more general negative sentiment amongst the public regarding clinical trials without remuneration that has been reported elsewhere. [55] Perhaps some form of remuneration is necessary for trials such as this. Lastly, we may have been unable to maintain public awareness of the trial.

The attrition within the study was largely due to potential participants being deemed ineligible or not available at telephone screening (n = 254, 66% of screened callers).

We reviewed our eligibility criteria and decided that altering the criteria would impact the safety of the participants or enter participants with recent or concurrent use of the therapies under study. Our trial also required a 4-week baseline period and an 8-month commitment for full participation (to all follow-ups). Despite the low amount of actual contact time in the study, sufferers of TTH, a benign complaint that affects them only episodically, may have felt that these requirements were not attractive resulting in the substantial number of eligible people who cancelled or did not attend the intake evaluation (n = 55, 58% of those booked for intake).

Another limitation consists in the use of multiple treaters. It was not possible to provide chiropractic treatment in a single location, given the wide range of expected locations of subjects' work or residence. In using up to 8 chiropractors, we optimized the provision of chiropractic treatment across the catchment area of our trial; however, this may have introduced variation in the delivery of the trial protocol which may have influenced the results. In a larger trial, the effect of treatment location could be used as one factor in a mixed methods regression analysis. We declined to conduct this analysis on our small sample of enrollees. This regression model could include a variety of factors such as secondary outcomes of headache intensity, medication usage, health status, all of which are not included in the present analysis.

It is difficult to compare the results of our trial with those of Boline et al [37] and Bove and Nilsson, [38] because in each of those trials, the subjects in the groups receiving spinal manipulation were not blinded and the results from these groups were calculated directly from change scores within that group. Boline et al's trial appears closest to ours in that their TTH groups received either spinal manipulation or amitryptiline. Their finding that both groups demonstrated improvement at the end of the treatment phase of the study with no significant differences between these groups is somewhat analogous to our results with respect to the main effects of the individual treatments. In the case of our factorial design, the main effect of each of the treatments was calculated using data from all four study groups compared at the primary outcome end point (14 weeks post randomization). Only the effect of the combination group exceeded our level of clinically important difference; this is a finding that neither of the previous studies could have reported.

The effect obtained for the combined treatment in the adjusted analysis is of interest. Given the low number of subjects, a larger trial is needed to confirm this finding. Given the low incidence of adverse events in this trial, the combined treatment might present an optimal approach to the management of CTTH.

If the promising finding that the combination of these 2 therapies provides clinically important benefits is confirmed by future clinical trials, it would be consistent with the theoretical model proposed earlier, that is, that a clinical approach which addresses both the peripheral and central mechanisms purported to contribute to TTH may provide the largest clinical benefit.

Conclusion

We conducted a randomized, placebo-controlled, factorial clinical trial of chiropractic and medical therapies in primary care TTH subjects. Our trial was stopped early due to an inability to achieve its intended sample size. However, in our small sample, a clinically important, statistically significant benefit was found in the combination therapy group. This promising finding should be confirmed in a larger trial.

Practical Applications

No randomized, placebo-controlled trial exists of chiropractic treatment for TTH.

A factorial design was used in a clinical trial comparing chiropractic and medical treatments for TTH.

Recruitment was very difficult and resulted in a stopped trial.

The combination of chiropractic cervical manipulation and amitriptyline appears promising as a prophylactic treatment for TTH.